Once genetically engineered cells, such as stem cells designed to repair damaged tissues, immune cells programmed to recognize and destroy tumors, or hormone-producing cells for endocrine disorders, are delivered into a mammalian host, they become poorly controllable. This situation poses unprecedented risks associated with the predisposition of the engineered cells to transformation and/or malfunction. Drugs cannot distinguish between properly functioning and malfunctioning cells inside the body, while genetically build-in safety mechanisms may prove insufficient. Optogenetic approaches to control biological processes offer spatiotemporal resolution unmatched by chemicals, yet UV-visible light cannot reach deep mammalian tissues. In contrast, light in the near-infrared window is known to be safe and penetrate mammalian tissues to the depth of several centimeters, at least several-fold deeper than UV-visible light. Therefore, light from externally placed lasers or light guides inserted into body cavities can reach internal organs and control biological activitie. Bacteriophytochromes are the only class of photoreceptor proteins that sense near-infrared light. Bacteriophytochromes autocatalytically bind their chromophore (biliverdin) that is naturally made in mammalian cells. This fortunate circumstance obviates the need for exogenous chromophore supply. In this project we intend to engineer bacteriophytochrome-based genetic modules for orthogonal gene regulation in mammals, including humans. We plan to optimize these light-activated modules for several mouse tissues. The optogenetic tools developed here will allow researchers to execute conditional and reversible gene knockouts (or gene activation) in specific tissues of live animals, which will deepened our understanding of progression of various diseases, improve our knowledge of mammalian development, and offer real-time insights into host- pathogen interactions. These tools will also make gene and engineered cell therapies safer and smarter.